Haloalkylbenzoic acid esters having one or two halogen atoms on the alpha-carbon atom of the alkyl group are useful as chemical intermediates. For example, alkyl esters of 4-(bromomethyl)-benzoate such as the methyl or ethyl ester, are useful as intermediates in the synthesis of Eprosartan, (SKF-108566), a prototype of imidazoleacrylic acid angiotensin II receptor antagonists.
Few examples of radical bromination of p-toluic acid and its methyl and ethyl esters have appeared in the literature. See in this connection:
Listvan, V. N.; Stasyuk, A. P.; Kurgan, L. N., J. Gen. Chem. USSR, 1987, vol. 57, 1366 (English Translation); PA1 Chaintreau, A.; Adrian, G.; Coutrier, D., Synth. Commun., 1981, 11, 669; PA1 Houlihan, W. J.; Munder, P. G.; Handley, D. A.; Cheon, S. H.; Parrino, V. A., J. Med. Chem., 1995, 38, 234; PA1 Mamalis, P.; Green, J.; Outred, D. J.; Rix, M. J., J. Chem. Soc., 1965, 1829; PA1 King, F. E.; Grudon, M. F., J. Chem. Soc., 1950, 3547; PA1 Barany, G.; Albericio, F., J. Am. Chem. Soc., 1985, 107, 4936; and PA1 Marvel, C. S.; Kraiman, E. A., J. Org. Chem., 1953, 707.
In all of these prior processes, the bromination was carried out photochemically or by use of N-bromosuccinimide (NBS) or other bromine compound such as CuBr.sub.2. Only a single reference where bromine was used as bromination reagent to prepare ethyl 4-(bromomethyl)benzoate appeared some 70 years ago, and this involved an indirect two-step synthesis. Thus, Titley, A. F., J. Chem. Soc., 1928, 2571, describes treatment of p-toluolyl acid halides with bromine, followed by treatment with ethanol. p-Toluic acid itself was reportedly brominated at the benzylic position by bromine in nitrobenzene in 50% yield (Codington, J. F.; Mosettig, E., J. Org. Chem., 1952, 1035). No reference was found where the methyl or ethyl esters of p-toluic acid were directly converted to the corresponding benzylbromide by elemental bromine.
It was found possible in our laboratories to produce the methyl and ethyl esters of 4-(bromomethyl)benzoic acid photochemically using a sun lamp and bromine, and/or bromine/hydrogen peroxide in halogenated solvents in the presence of water. The product was recovered by recrystallization from aqueous ethanol or 2-propanol. This, however, is not a commercially viable process for operation on an industrial scale. Likewise, brominations using bromine compounds such as NBS or dibromodimethylhydantoin (DBDMH) suffer not only from the relatively high cost of the bromine sources, but from the formation of organic waste composed of coproduct amides.
A process enabling direct production of methyl or ethyl 4-(bromomethyl)benzoate in one step and in good yield by bromination of the ester of p-toluic acid with bromine would be commercially desirable. It was found, however, from attempts to carry out such direct bromination that there is a complicating factor--that of the tendency for the bromine to cause ester cleavage under thermal bromination conditions.
A need exists for an effective process enabling the direct one-step synthesis of mono- and dihaloalkylbenzoic acid esters with the halogen atom(s) on the alpha-carbon atom of the alkyl group, using bromine and a primary alkylbenzoic acid ester as the reactants. Such a process, if attainable, would avoid the shortcomings noted above.
This invention is deemed to have fulfilled this need.